Principal Investigator/Program Director (Last, first, middle): Elich, Tedd, Danilo PROJECT SUMMARY Acetyl-CoA carboxylase (ACC) catalyzes the first step in fatty acid biosynthesis and its product, malonyl-CoA, inhibits fatty acid oxidation. These functions make ACC a prime target for the development of therapeutics to treat obesity and type 2 diabetes. Knockout studies in mice, and animal studies with ACC inhibitors, have validated this approach. The most potent inhibitor of eukaryotic ACCs identified to date is the natural product soraphen. Soraphen has been demonstrated to have pharmacological properties consistent with the potential to treat obesity and diabetes; however, soraphen is not suitable as a therapeutic due to toxic side effects. Furthermore, soraphen is not a good starting point for drug development due to its complex structure. We propose to identify novel small molecules that target the soraphen binding